The recent demonstration of pharmacologically relevant receptor sites for the benzodiazepines in brain provide insight into the molecular mechanism of action of these drugs. The presence of receptor sites for benzodiazepines predicts the existence of naturally occurring ligands. Studies from our laboratory have shown that the purines specifically inhibit 3(H) diazepam binding to brain receptor sites, that they possess "benzodiazepine-like" pharmacologic and neurophysiologic properties, and that structure-activity relationships exist. Inosine has been shown to antagonize seizures produced by caffeine, suggesting that the benzodiazepine receptors and their putative endogenous ligands may be involved in seizure modification. Several higher molecular weight benzodiazepine receptor ligands have also been isolated, although they have not yet been identified. Recent studies have centered on the interaction of the GABA and benzodiazepine receptors: both the purines and benzodiazepines have been shown to be potent inhibitors of 3(H) diazepam binding, as are the methylxanthine stimulants caffeine and theophylline. Furthermore, these compounds have been shown to be an order of magnitude more potent as inhibitors of GABA-stimulated diazepam binding compared with basal binding.